Abstract:

Disclosed is a process for producing a protected optically active
fluoroamine, which comprises the step of reacting an imine-protected
optically active hydroxyamine, an oxazolidine-protected optically active
hydroxyamine, or a mixture of the imine-protected optically active
hydroxyamine and the oxazolidine-protected optically active hydroxyamine,
with sulfuryl fluoride (SO2F2) in the presence of a tertiary
amine having a carbon number of 7 to 18 (produced by substituting all of
three hydrogen atoms in ammonia by alkyl groups). The desired optically
active fluoroamine can be produced by hydrolyzing the protected optically
active fluoroamine under acidic conditions.

Claims:

1. A process for producing a protected optically active fluoroamine of the
formula [3], comprising:reacting an imine-protected optically active
hydroxyamine of the formula [1], an oxazolidine-protected optically
active hydroxyamine of the formula [2] or a mixture thereof with sulfuryl
fluoride (SO2F2) in the presence of a tertiary amine in which
all of three ammonia hydrogen atoms have been replaced by alkyl groups
and which has a carbon number of 7 to 18 ##STR00028## where R1 and
R2 each independently represent an alkyl group or an aromatic ring
group; * represents an asymmetric carbon; the stereochemistry of the
asymmetric carbon is maintained through the reacting; and the wavy line
indicates in the formula (1) and in the formula (3) that the
nitrogen-carbon group is in an E-configuration, a Z-configuration or a
mixture thereof and indicates in the formula (2) that the substituent
group R1 is in a syn-configuration, an anti-configuration or a
mixture thereof.

2. The process for producing the protected optically active fluoroamine
according to claim 1, wherein R2 of the imine-protected optically
active hydroxyamine of the formula [1] or the oxazolidine-protected
optically active hydroxyamine of the formula [2] is an aromatic
hydrocarbon group; and the tertiary amine has a carbon number of 8 to 12
and contains two or more alkyl groups of 3 or more carbon atoms.

3. The process for producing the protected optically active fluoroamine
according to claim 1 or 2, comprising forming the imine-protected
optically active hydroxyamine of the formula [1] or the
oxazolidine-protected optically active hydroxyamine of the formula [2] by
dehydrative condensation of an optically active hydroxyamine of the
formula [4] and an aldehyde of the formula [5] ##STR00029## where R1
and R2 each independently represent an alkyl group or an aromatic
ring group; and * represents an asymmetric carbon of which the
stereochemistry is maintained through the dehydrative condensation.

4. The process for producing the protected optically active fluoroamine
according to claim 3, wherein R1 is an alkyl group having 1 to 9
carbon atoms in the formula [4].

5. The process for producing the protected optically active fluoroamine
according to claim 3, wherein the dehydrative condensation is preformed
in the presence of an acid catalyst.

6. The process for producing the protected optically active fluoroamine
according to claim 5, wherein the acid catalyst is either
para-toluenesulfonic acid or pyridinium para-toluenesulfonate.

7. The process for producing the protected optically active fluoroamine
according to claim 1, wherein the tertiary amine is
diisopropylethylamine.

8. A process for producing an optically active fluoroamine of the formula
[6], comprising: performing, under acidic conditions, hydrolysis of the
protected optically active fluoroamine of the formula [3] produced by the
process according to claim 1 ##STR00030## where R1 represents an
alkyl group or an aromatic ring group; and * represents an asymmetric
carbon of which the stereochemistry is maintained through the hydrolysis.

9. The process for producing the optically active fluoroamine according to
claim 8, wherein the hydrolysis is performed by reacting the protected
optically active fluoroamine of the formula [3] with an aqueous solution
of an acid catalyst; and the acid catalyst is either hydrogen chloride or
sulfuric acid.

10. A protected optically active fluoroamine of the formula [3]
##STR00031## where R1 and R2 each independently represent an
alkyl group or an aromatic ring group; * represents an asymmetric carbon;
and the wavy line indicates that the nitrogen-carbon double bond is in an
E-configuration, a Z-configuration or a mixture thereof.

Description:

[0001]The present invention relates to an industrial production process of
an optically active fluoroamine, which is important as an intermediate of
pharmaceutical and agrichemical products.

BACKGROUND ART

[0002]An optically active fluoroamine, which is the target of the present
invention, is an important intermediate of pharmaceutical and
agrichemical products. The direct production of the optically active
fluoroamine is generally conducted by dehydroxyfluorination of a
corresponding optically active amino alcohol in a protected amino form.

[0003]The present applicant has disclosed a process for producing an
optically active fluoroamine by dehydroxyfluorination of an alcohol with
the combined use of sulfuryl fluoride (SO2F2) and an organic
base. This production process provides a target fluorinated compound
(phthaloyl-protected form) with a yield of 23% in the case of using as a
raw material an optically active amino alcohol of which the amino group
(--NH2) has been protected with a phthaloyl group (cf. Scheme 1:
Patent Document 1).

##STR00001##

[0004]Further, there is known a process for dehydroxyfluorination of an
optically active amino alcohol in a protected amino form using a
fluorination agent known as Deoxo-Fluor® (cf. Scheme 2: Non-Patent
Document 1) or DAST (cf. Scheme 3: Non-Patent Document 2).

[0008]It is an object of the present invention to provide an industrial
production process of an optically active fluoroamine.

[0009]It is known that the dehydroxyfluorination of the protected
optically active amino alcohol involves neighboring-group participation
of a nitrogen atom even when the amino group has been protected with a
protecting group. For example, the dehydroxyfluorination reaction of a
substrate having the same 1,2-amino alcohol structure as that in the
present invention and containing a dibenzyl group as an amino protecting
group cannot selectively produce a target compound with a fluorine atom
simply substituted on its hydroxyl-bonded carbon atom and provides a
rearranged form of the target compound as a main product (cf. Schemes 2
and 3).

[0010]The dehydroxyfluorination reaction of Patent Document 1, in which
the phthaloyl-protected amino alcohol is dehydroxyfluorinated with
sulfuryl fluoride, can limit neighboring-group participation of a
nitrogen atom and produce the target compound by a relatively easy
operation. The product yield is however merely 23% and is susceptible to
improvement. Further, the reaction system is placed under basic
conditions by the addition of hydrazine as a typical phthaloyl
deprotecting agent. In such a basic reaction system, there occurs a side
reaction between the deprotected amino group (nucleophilic moiety) and
fluorine atom (electrophilic moiety) of the target compound. This results
in a low deprotection yield without being able to prevent the target
compound from intramolecular ring-closure to an aziridine, intermolecular
polycondensation and hydrazine substitution etc. In view of the above
facts that: the desired dehydroxyfluorination reaction does not proceed
favorably under the disclosed reaction conditions; and the deprotection
of the resultant fluorinated compound does not proceed selectively, it
cannot always be said that the dehydroxyfluorination reaction of Patent
Document 1 is practical for the production of the target optically active
fluoroamine of the present invention.

[0011]Furthermore, the dehydroxyfluorination agents such as
Deoxo-Fluor® and DAST are expensive and have a danger of explosion
whereby the use of these dehydroxyfluorination agents is limited to
small-scale production purposes. There is thus a strong demand for a
reaction agent that is not only capable of performing a desired
dehydroxyfluorination reaction favorably but also suitable for
large-scale production uses.

[0012]As described above, it has been demanded to develop a
high-selectivity, high-yield production process suitable for mass
production of an optically active fluoroamine of the after-mentioned
formula [6]. In order to satisfy such a demand, it is important to find
out an amino protecting group capable of preventing neighboring-group
participation of the nitrogen atom effectively and enabling easy
protection and deprotection of the amino group. It is also necessary to
clarify reaction conditions under which the dehydroxyfluorination of the
protected amino form proceeds favorably.

[0013]As a result of extensive researches made in view of the above
problems, the present inventors have found that: the selection of an
amino protecting group for an optically active hydroxyamine is important;
and an imine-protected optically active hydroxyamine (hereinafter
occasionally simply referred to as "imine form") of the present invention
can be easily prepared by dehydrative condensation of an optically active
hydroxyamine and an aldehyde and undergoes a desired
dehydroxyfluorination reaction favorably with almost no side reaction
such as rearrangement due to neighboring group participation of its
nitrogen atom. The present inventors have also found that, although there
is a difficulty in obtaining the imine form selectively by dehydrative
condensation of the optically active hydroxyamine and the aldehyde, an
oxazolidine-protected optically active hydroxyamine (hereinafter
occasionally simply referred to as "oxazolidine form") generated as a
by-product of the dehydrative condensation also serves as a suitable
substrate in the dehydroxyfluorination reaction of the present invention
(cf. Scheme 4).

##STR00004##

[0014]The present inventors have further found that: the protected
optically active fluoroamine obtained by the dehydroxyfluorination
reaction can be easily deprotected by hydrolysis under acidic conditions;
and, in contrast to the above-mentioned phthaloyl deprotection reaction
under the basic conditions, the deprotection reaction under the acidic
conditions makes it possible to limit nucleophilicity by protonation of
the deprotected amino group and thus proceeds selectively with almost no
side reaction.

[0015]For the above reasons, both of the imine form and the oxazolidine
form are suitable protected amino forms in the present invention. In
these protected amino forms, R2 is particularly preferably an
aromatic hydrocarbon group in view of the large-scale availability of the
raw aldehyde material, the ease and selectivity of protection and
deprotection of the amino group, the effect of preventing the reactivity
of dehydroxyfluorination of the hydroxyamine and the neighboring-group
participation of the nitrogen atom, the large-scale handling stability of
various intermediates and the like.

[0016]On the other hand, the present inventors have found that: even if
the suitable protected amino form, i.e., the imine form, oxazolidine form
or mixture thereof is reacted with sulfuryl fluoride in the presence of
triethylamine, which is heavily used as a typical organic base in Patent
Document 1, the desired dehydroxyfluorination reaction does not proceed
favorably; and the triethylamine nucleophilically attacks a
fluorosulfuric acid ester intermediate in preference to the fluorine
anion (F.sup.-) so that there occurs a large amount of quaternary
ammonium salt as a by-product (cf. Comparative Example 1; Scheme 5).

##STR00005##

[0017]Under these circumstances, the present inventors have focused
attention on the steric effect of an organic base and have found that the
use of a tertiary amine having a carbon number of 7 to 18, preferably a
tertiary amine having a carbon number of 8 to 12 and containing two or
more alkyl groups of 3 or more carbon atoms (such as
diisopropylethylamine, tri-n-butylamine etc.), as the organic base makes
it possible to effectively prevent the generation of a quaternary
ammonium salt as a by-product. The desired steric effect of the tertiary
amine can be obtained sufficiently when the tertiary amine has a carbon
number of up to 18. The carbon number of the tertiary amine is thus
preferably up to 18, more preferably up to 12, in view of the large-scale
availability of the amine, the productivity of the dehydroxyfluorination
reaction system and the like.

[0018]Consequently, the present inventors have verified that it is
important to use the suitable protected amino form in combination with
the above specific tertiary amine for production of the target optically
active fluoroamine of the present invention.

[0019]The present inventors have finally found a novel protected optically
active fluoroamine as a useful key intermediate in the present invention.

[0020]As described above, the present inventors have found the
particularly useful techniques for industrial production of the optically
active fluoroamine. The present invention is based on these findings.

[0021]According to the present invention, there is provided a process
(first process) for producing a protected optically active fluoroamine of
the formula [3], comprising: reacting an imine-protected optically active
hydroxyamine of the formula [1], an oxazolidine-protected optically
active hydroxyamine of the formula [2] or a mixture thereof with sulfuryl
fluoride (SO2F2) in the presence of a tertiary amine (in which
all of three ammonia hydrogen atoms have been replaced by alkyl groups)
having a carbon number of 7 to 18

##STR00006##

where R1 and R2 each independently represent an alkyl group or
an aromatic ring group: * represents an asymmetric carbon; the
stereochemistry of the asymmetric carbon is maintained through the
reaction; and the wavy line indicates in the formula (1) and in the
formula (3) that the nitrogen-carbon double bond is in an
E-configuration, a Z-configuration or a mixture thereof and indicates in
the formula (2) that the substituent group R1 is in a
syn-configuration, an anti-configuration or a mixture thereof.

[0022]The first process may be a process (second process) for producing
the protected optically active fluoroamine, in which: R2 of the
imine-protected optically active hydroxyamine of the formula [1] or the
oxazolidine-protected optically active hydroxyamine of the formula [2] is
an aromatic hydrocarbon group; and the tertiary amine has a carbon number
of 8 to 12 and contains two or more alkyl groups of 3 or more carbon
atoms.

[0023]The first or second process may be a process (third process) for
producing the protected optically active fluoroamine, in which the
imine-protected optically active hydroxyamine of the formula [1] or the
oxazolidine-protected optically active hydroxyamine of the formula [2] is
obtained by dehydrative condensation of an optically active hydroxyamine
of the formula [4] and an aldehyde of the formula [5]

##STR00007##

where R1 and R2 each independently represent an alkyl group or
an aromatic ring group; and * represents an asymmetric carbon of which
the stereochemistry is maintained through the dehydrative condensation.

[0024]There is also provided according to the present invention a process
(fourth process) for producing an optically active fluoroamine of the
formula [6], comprising: performing, under acidic conditions, hydrolysis
of the protected optically active fluoroamine of the formula [3] produced
by either one of the first to third processes

##STR00008##

where R1 represents an alkyl group or an aromatic ring group; and *
represents an asymmetric carbon of which the stereochemistry is
maintained through the hydrolysis.

[0025]There is further provided according to the present invention a
protected optically active fluoroamine of the formula [3]

##STR00009##

where R1 and R2 each independently represent an alkyl group or
an aromatic ring group; * represents an asymmetric carbon; and the wavy
line indicates that the nitrogen-carbon double bond is in an
E-configuration, a Z-configuration or a mixture thereof.

[0026]In the formula [3], R2 may be an aromatic hydrocarbon group.

DETAILED DESCRIPTION

[0027]The advantages of the present invention over the prior art
technologies will be explained below.

[0028]The present invention is advantageous over Patent Document 1, in
that it is possible in the present invention to improve the yield of the
dehydroxyfluorination reaction significantly and to enable selective,
high-yield deprotection of the resultant fluorinated compound.

[0029]The present invention is advantageous over Non-Patent Documents 1
and 2, in that it is possible in the present invention to limit the
occurrence of a side reaction due to neighboring-group participation of
the nitrogen atom and to adopt the dehydroxyfluorination agent suitable
for large-scale production purposes. Sulfuryl fluoride used in the
present invention has widely been applied as a fumigant and can easily be
processed to an inorganic salt waste such as fluorite (CaF2) or
calcium sulfate.

[0030]All of the raw materials and reaction agents used in the present
invention are available in large quantities and at relatively low cost.
Further, the target compound can be produced with high chemical purity
and high yield and with almost no by-product generation as all of the
reaction steps are conducted under moderate reaction conditions. In
addition, the stereochemistry of the asymmetric carbon can be maintained
throughout the reaction steps so that the use of the raw material of
higher optical purity leads to higher optical purity of the target
compound.

[0031]The production process of the present invention is therefore
industrially readily practicable and can solve all of the above-mentioned
prior art problems.

[0032]The production process of the optically active fluoroamine according
to the present invention will be described in detail below. In the
present invention, the production process includes: a first step
(dehydrative condensation reaction) for forming a protected optically
active hydroxyamine of the formula [1] or [2] (imine form, oxazolidine
form or mixture thereof) by dehydrative condensation of an optically
active hydroxyamine of the formula [4] and an aldehyde of the formula
[5]; a second step (dehydroxyfluorination reaction) for reacting the
protected optically active hydroxyamine of the formula [1] or [2] (imine
form, oxazolidine form or mixture thereof) with sulfuryl fluoride in the
presence of a tertiary amine having a carbon number of 7 to 18, thereby
converting the protected optically active hydroxyamine to a protected
optically active fluoroamine of the formula [3]; and a third step
(hydrolysis reaction) for forming an optically active fluoroamine of the
formula [6] by hydrolysis of the protected optically active fluoroamine
of the formula [3] under acidic conditions (cf. Scheme 6).

##STR00010##

[0033]The first step (dehydrative condensation reaction) will be first
explained in detail below.

[0034]In the optically active hydroxyamine of the formula [4], R1
represents an alkyl group or an aromatic ring group. As the alkyl group,
there can be used those having 1 to 18 carbon atoms and having a linear
structure, a branched structure or a cyclic structure (in the case of 3
or more carbons). (The cyclic structure may be a monocyclic structure, a
condensed polycyclic structure, a crosslinked structure, a spiro ring
structure, a ring assembly structure or the like.) Any of the carbon
atoms of the alkyl group may be replaced by any number of and any
combination of hetero atoms such as nitrogen, oxygen and sulfur. (The
nitrogen atom may have an alkyl group, an aromatic ring group, a
protecting group or the like as a substituent; and the sulfur atom may
have an oxygen atom as a substituent (--SO-- or --SO2--).) Two
hydrogen atoms bonded to any (one) of the carbon atoms of the alkyl group
may be replaced by any number of and any combination of nitrogen, oxygen
and sulfur atoms. (In this case, the nitrogen, oxygen and/or sulfur atom
forms an imino moiety, a carbonyl moiety or a thiocarbonyl moiety
together with the carbon atom; and the nitrogen atom may have an alkyl
group, an aromatic ring group, a protecting group or the like as a
substituent.) Further, any adjacent two of the carbon atoms of the alkyl
group may be replaced by any number of and any combination of unsaturated
groups (double bond or triple bond). As the aromatic ring group, there
can be used those having 1 to 18 carbon atoms, such as aromatic
hydrocarbon groups, e.g., phenyl, naphthyl, anthryl etc. and aromatic
heterocyclic groups containing heteroatoms such as nitrogen, oxygen and
sulfur, e.g., pyrrolyl, furyl, thienyl, indolyl, benzofuryl, benzothienyl
etc. (The nitrogen atom may have an alkyl group, an aromatic ring group,
a protecting group or the like as a substituent; and the aromatic
heterocyclic group may have a monocyclic structure, a condensed
polycyclic structure, a ring assembly structure or the like.)

[0035]The alkyl group or aromatic ring group may have any number of and
any combination of substituents on any of the carbon atoms thereof.
Examples of the substituents are: halogen atoms such as fluorine,
chlorine, bromine and iodine; azide group; nitro group; lower alkyl
groups such as methyl, ethyl and propyl; lower haloalkyl groups such as
fluoromethyl, chloromethyl and bromomethyl; lower alkoxy groups such as
methoxy, ethoxy and propoxy; lower haloalkoxy groups such as
fluoromethoxy, chloromethoxy and bromomethoxy; lower alkylamino groups
such as dimethylamino, diethylamino and dipropylamino; lower alkylthio
groups such as methylthio, ethylthio and propylthio; cyano group; lower
alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl and
propoxycarbonyl; aminocarbonyl group (CONH2); lower aminocarbonyl
groups such as dimethylaminocarbonyl, diethylaminocarbonyl and
dipropylaminocarbonyl; unsaturated groups such as alkenyl and alkynyl;
aromatic ring groups such as phenyl, naphthyl, pyrrolyl, furyl and
thienyl; aromatic ring oxy groups such as phenoxy, naphthoxy,
pyrrolyloxy, furyloxy and thienyloxy; aliphatic heterocyclic groups such
as piperidyl, piperidino and morpholinyl; protected hydroxyl groups;
protected amino groups (including amino acids and peptide residues);
protected thiol groups; protected aldehyde groups; protected carboxyl
groups; and the like.

[0036]In the present specification, the following terms have the following
meanings. The term "lower" means that the group to which the term is
attached has 1 to 6 carbon atoms and has a linear structure, a branched
structure or a cyclic structure (in the case of 3 carbons or more). It
means that, when the "unsaturated group" is a double bond (alkenyl
group), the double bond can be in an E-configuration, a Z-configuration
or a mixture thereof. It means that the "protected hydroxyl, amino
(including amino acid or peptide residue), thiol, aldehyde and carboxyl
groups" may be those having protecting groups described in "Protective
Groups in Organic Synthesis", Third Edition, 1999, John Wiley & Sons,
Inc. and the like. (In this case, two or more functional groups may be
protected with one protecting group.)

[0038]Although the alkyl group or aromatic ring group is suitably used as
R1 in the optically active hydroxyamine of the formula [4], R1
is preferably the alkyl group of 1 to 9 carbon atoms. The optically
active hydroxyamine in which R1 is the alkyl group of 1 to 9 carbon
atoms is preferred in that: a raw material of the optically active
hydroxyamine, i.e., an optically active α-amino acid is easily
available on a large scale; and the optically active hydroxyamine can be
easily prepared by reduction of the optically active α-amino acid.
The optically active hydroxyamine in which R' is the alkyl group of 1 to
6 is commercially available in various forms and is thus particularly
preferred as the starting material of the present invention.

[0039]In the optically active hydroxyamine of the formula [4], *
represents an asymmetric carbon. The stereochemistry (absolute
configuration and optical purity) of the asymmetric carbon is maintained
through the dehydrative condensation reaction.

[0040]The absolute configuration of the asymmetric carbon can be either a
R-configuration or a S-configuration and be set appropriately depending
on the absolute configuration of the target optically active fluoroamine
of the formula [6].

[0041]The optical purity of the asymmetric carbon can be indicated by
enantiomer excess (ee). It suffices that the enantiomer excess is 80% ee
or higher in view of the use of the target optically active fluoroamine
of the formula [6] as a pharmaceutical/agrichemical intermediate. The
enantiomer excess is generally preferably 90% ee or higher, more
preferably 95% ee or higher.

[0042]In the aldehyde of the formula [5], R2 represents an alkyl
group or an aromatic ring group.

[0043]Examples of the alkyl group or aromatic ring group R2 are the
same as R1 in the optically active hydroxyamine of the formula [4].
Among others, aromatic hydrocarbon groups are preferred. Particularly
preferred are phenyl, substituted phenyl, naphthyl and substituted
naphthyl. The aldehyde in which R2 is phenyl, substituted phenyl,
naphthyl or substituted naphthyl has the advantage of being industrially
available at low cost in addition to the advantage of the use of the
aromatic hydrocarbon group as R2 described above in "Means for
Solving the Problems".

[0044]It suffices to use the aldehyde of the formula [5] in an amount of
0.7 mol or more per 1 mol of the optically active hydroxyamine of the
formula [4]. The amount of the aldehyde of the formula [5] used is
generally preferably in the range of 0.8 to 5 mol, more preferably 0.9 to
3 mol, per 1 mole of the optically active hydroxyamine of the formula
[4].

[0045]In the first step, the reaction is performed preferably in the
presence of an acid catalyst or under dehydrative conditions. Depending
on the combination of the raw substrate materials, the reaction may
proceeds favorably even without the adoption of these reaction
conditions.

[0046]Examples of the acid catalyst are: inorganic acids such as hydrogen
chloride (hydrochloric acid), sulfuric acid, phosphoric acid, zinc
chloride, titanium tetrachloride and tetraisopropoxy titanium; and
organic acids such as benzenesulfonic acid, para-toluenesulfonic acid,
pyridinium para-toluenesulfonate (PPTS) and 10-camphorsulfonic acid.
Among others, sulfuric acid, para-toluenesulfonic acid and pyridinium
para-toluenesulfonate (PPTS) are preferred. Particularly preferred are
para-toluenesulfonic acid and pyridinium para-toluenesulfonate (PPTS). It
suffices to use a catalytic amount of the acid catalyst per 1 mol of the
optically active hydroxyamine of the formula [4]. The amount of the acid
catalyst used is generally preferably in the range of 0.001 to 0.7 mol,
more preferably 0.005 to 0.5 mol, per 1 mol of the optically active
hydroxyamine of the formula [4].

[0047]Further, the reaction under the dehydrative conditions can be
performed by using, as a reaction solvent, an aromatic hydrocarbon
solvent that is inmiscible with water, lower in specific gravity than
water and azeotropic with water, and refluxing the reaction system while
removing by-product water with a Dean-Stark trap.

[0048]Examples of the reaction solvent are: aliphatic hydrocarbon solvents
such as n-hexane, cyclohexane and n-heptane; aromatic hydrocarbon
solvents such as benzene, toluene, ethylbenzene, xylene and mesitylene;
halogenated hydrocarbon solvents such as methylene chloride, chloroform
and 1,2-dichloroethane; ether solvents such as diethyl ether,
tetrahydrofuran, diisopropyl ether and tert-butyl methyl ether; ester
solvents such as ethyl acetate and n-butyl acetate; amide solvents such
as N,N-dimethylformamide, N,N-dimethylacetoamide, N-methyl-pyrrolidone
and 1,3-dimethyl-2-imidazolidinone; nitrile solvents such as acetonitrile
and propionitrile; dimethyl sulfoxide; and the like.

[0049]Among others, n-hexane, n-heptane, toluene, xylene, mesitylene,
methylene chloride, tetrahydrofuran, diisopropyl ether, tert-butyl methyl
ether, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetoamide,
acetonitrile, propionitrile and dimethyl sulfoxide are preferred.
Particularly preferred are toluene, xylene, methylene chloride,
tetrahydrofuran, diisopropyl ether, ethyl acetate, N,N-dimethylformamide
and acetonitrile. These reaction solvents can be used alone or in
combination thereof. Alternatively, the reaction may be performed in the
absence of the reaction solvent in the first step.

[0050]It suffices to use the reaction solvent in an amount of 0.01 L
(liter) or more per 1 mol of the optically active hydroxyamine of the
formula [4]. The amount of the reaction solvent used is generally
preferably in the range of 0.05 to 5 L, more preferably 0.1 to 3 L, per 1
mol of the optically active hydroxyamine of the formula [4].

[0051]Further, it suffices that the temperature condition ranges from -20
to +200° C. The temperature condition is generally preferably in
the range of -10 to +175° C., more preferably 0 to +150° C.

[0052]The reaction time is generally 72 hours or less. As the reaction
time depends on the combination of the raw substrate materials and the
adopted reaction conditions, it is preferable to determine the time at
which the raw substrate materials have almost disappeared as the end of
the reaction while monitoring the progress of the reaction by any
analytical means such as gas chromatography, thin-layer chromatography,
liquid chromatography or nuclear magnetic resonance.

[0053]The target protected optically active hydroxyamine of the formula
[1] or [2] can be obtained as the imine form, ozazolidine form or mixture
thereof by ordinary post treatment of the reaction-terminated liquid.
Herein, the nitrogen-carbon double bond of the imine form is in an
E-configuration, a Z-configuration or a mixture thereof; and the
oxazolidine form is in a syn-configuration, an anti-configuration or a
mixture thereof with respect to the substituent group R1. Although
the ratio of these isomers depends on the combination of the raw
substrate materials and the adopted reaction conditions, the
dehydroxyfluorination reaction of the second step proceeds favorably
without the influence of such an isomer ratio. Further, the target
compound can be purified to a high chemical purity, as needed, by
purification operation such as activated carbon treatment, distillation,
recrystallization or column chromatography.

[0054]In the first step, the reaction proceeds favorably with high
selectivity. It is thus possible to obtain the target compound of
sufficient quality as the raw substrate material for the
dehydroxyfluorination reaction of the second step only by evaporating the
reaction solvent for removal of the by-product water. Such simple post
treatment is suitable in view of industrial production uses. Next, the
second step (dehydroxyfluorination reaction) will be explained in detail
below.

[0055]It suffices to use the sulfuryl fluoride (SO2F2) in an
amount of 0.7 mol or more per 1 mol of the protected optically active
hydroxyamine of the formula [1] or [2] (imine form, oxazolidine form or
mixture thereof). The amount of the sulfuryl fluoride used is generally
preferably in the range of 0.8 to 10 mol, more preferably 0.9 to 5 mole,
per 1 mol of the protected optically active hydroxyamine derivative of
the formula [1] or [2].

[0056]In the second step, trifluoromethanesulfonyl fluoride
(CF3SO2F) or perfluorobutanesulfonyl fluoride
(C4F9SO2F) may alternatively be used as the
dehydroxyfluorination agent. There is however no particular advantage to
using these reaction agents in view of their large-scale availability,
waste disposal and the like.

[0057]As already explained above, it is important in the second step to
perform the reaction in the presence of the tertiary amine of carbon
number 7 to 18. In the present specification, the term "carbon number"
refers to a total number of carbons of three alkyl groups; and the term
"tertiary amine" refers to an amine in which all of three hydrogen atoms
of ammonia have been replaced by alkyl groups. The tertiary amine of
carbon number 7 to 18 has alkyl groups, each of which is either linear,
branched or cyclic (in the case of 3 carbons or more). It is particularly
preferable that the tertiary amine has a carbon number of 8 to 12 and
contains two or more alkyl groups of 3 or more carbon atoms.

[0058]Preferred examples of the tertiary amine are: diisopropylethylamine
(having a carbon number of 8 and containing two alkyl groups of 3 or more
carbon atoms); tri-n-propylamine (having a carbon number of 9 and
containing three alkyl groups of 3 or more carbon atoms);
diisopropylisobutylamine (having a carbon number of 10 and containing
three alkyl groups of 3 or more carbon atoms); di-n-butylisopropylamine
(having a carbon number of 11 and containing three alkyl groups of 3 or
more carbon atoms); tri-n-butylamine (having a carbon number of 12 and
containing three alkyl groups of 3 or more carbon atoms); and the like.
Among others, diisopropylethylamine and tri-n-butylamine are preferred.
Particularly preferred is diisopropylethylamine. The tertiary amine is
suitable for industrial production uses as it has high lipophilicity and
thus can be easily recovered and recycled without reactivity
deterioration.

[0059]It suffices to use the tertiary amine of carbon number 7 to 18 in an
amount of 0.7 mol or more per 1 mol of the protected optically active
hydroxyamine of the formula [1] or [2] (imine form, oxazolidine form or
mixture thereof). The amount of the tertiary amine used is generally
preferably in the range of 0.8 to 10 mol, more preferably 0.9 to 5 mol,
per 1 mole of the protected optically active hydroxyamine of the formula
[1] or [2].

[0060]In the second step, the reaction may be performed in the presence of
"a salt or complex of a tertiary amine having a carbon number of 7 to 18
and hydrogen fluoride". However, the reaction proceeds favorably even in
the absence of such a salt or complex. There is thus no need to perform
the reaction in the presence of the salt or complex.

[0061]The same reaction solvent as that in the first step (dehydrative
condensation reaction) can be used in the second step. Preferred examples
and particularly preferred examples of the reaction solvent in the second
step are also the same as those in the first step. The reaction solvents
can be used alone or in combination thereof. Alternatively, the reaction
may be performed in the absence of the reaction solvent in the second
step.

[0062]It suffices to use the reaction solvent in an amount of 0.1 L
(liter) or more per 1 mol of the protected optically active hydroxyamine
of the formula [1] or [2] (imine form, oxazolidine form or mixture
thereof). The amount of the reaction solvent used is generally preferably
in the range of 0.2 to 10 L, more preferably 0.3 to 5 L, per 1 mol of the
protected optically active hydroxyamine of the formula [1] or [2].

[0063]It suffices that the temperature condition ranges from -100 to
+100° C. The temperature condition is generally preferably in the
range of -50 to +50° C., more preferably -40 to +40° C. In
the case where the temperature condition is set to be higher than or
equal to a boiling point (-49.7° C.) of the sulfuryl fluoride, the
reaction can be conducted using a pressure-proof reaction vessel.

[0064]It suffices that the pressure condition ranges from atmospheric
pressure to 2 MPa. The pressure condition is generally preferably in the
range of atmospheric pressure to 1.5 MPa, more preferably atmospheric
pressure to 1 MPa. It is thus preferable to conduct the reaction using a
pressure-proof reaction vessel made of a stainless steel (SUS) material,
a glass (glass-lined) material or the like. Further, it is efficient for
large-scale charging of the sulfuryl fluoride into the pressure-proof
reaction vessel to develop a negative pressure atmosphere in the reaction
vessel, and then, introduce the sulfuryl fluoride in gas or liquid form
under vacuum while increasing the pressure.

[0065]The reaction time is generally 72 hours or less. As the reaction
time depends on the combination of the raw substrate material and the
tertiary amine of carbon number 7 to 18 and the adopted reaction
conditions, it is preferable to determine the time at which the raw
substrate material has almost disappeared as the end of the reaction
while monitoring the progress of the reaction by any analytical means
such as gas chromatography, thin-layer chromatography, liquid
chromatography or nuclear magnetic resonance.

[0066]The target protected optically active fluoroamine of the formula [3]
can be obtained by ordinary post treatment of the reaction-terminated
liquid. Further, the target compound can be purified to a high chemical
purity, as needed, by purification operation such as activated carbon
treatment, distillation, recrystallization or column chromatography.

[0067]One effective technique of the post treatment is to concentrate the
reaction-terminated liquid, dilute the concentration residue with an
organic solvent such as toluene or ethyl acetate, wash the residue with
an aqueous solution of an inorganic base such as potassium carbonate,
further wash the residue with water, and then, concentrate the recovered
organic phase. It is possible by such post treatment to obtain the target
compound of sufficient quality as the raw substrate material for the
hydrolysis reaction of the third step.

[0068]Finally, the third step (hydrolysis reaction) will be explained in
detail below.

[0069]In the third step, the hydrolysis reaction is performed under the
acidic condition. More specifically, the hydrolysis reaction can be
performed by reacting the protected optically active fluoroamine of the
formula [3] with an aqueous solution of an acid catalyst.

[0070]Examples of the acid catalyst are: inorganic acids such as hydrogen
chloride, hydrogen bromide, hydrogen iodide, sulfuric acid and nitric
acid; and organic acids such as formic acid, acetic acid, benzenesulfonic
acid and paratoluenesulfonic acid. Among others, inorganic acid are
preferred. Particularly preferred are hydrogen chloride and sulfuric
acid. It suffices to use the acid catalyst in an amount of 0.1 mol or
more per 1 mole of the protected optically active fluoroamine of the
formula [3]. The amount of the acid catalyst used is generally preferably
in the range of 0.3 to 30 mol, more preferably 0.5 to 20 mol, per 1 mole
of the protected optically active fluoroamine of the formula [3].

[0071]Further, it suffice to use water in an amount of 1 mol or more per 1
mol of the protected optically active fluoroamine of the formula [3]. The
amount of the water used is generally preferably in the range of 3 to 300
mol, more preferably 5 to 150 mol, per 1 mole of the protected optically
active fluoroamine of the formula [3].

[0072]Examples of the reaction solvent are: aliphatic hydrocarbon solvents
such as n-hexane, cyclohexane and n-heptane; aromatic hydrocarbon
solvents such as benzene, toluene, ethylbenzene, xylene and mesitylene;
ether solvents such as diethyl ether, tetrahydrofuran, diisopropyl ether
and tert-butyl methyl ether; and alcohol solvents such as methanol,
ethanol, n-propanol and isopropanol; and the like. Among others,
n-hexane, n-heptane, toluene, xylene, diisopropyl ether, methanol,
ethanol and isopropanol are preferred. Particularly preferred are
n-heptane, toluene, xylene and methanol. These reaction solvents can be
used alone or in combination thereof. Alternatively, the reaction may be
performed in the absence of the reaction solvent or in two-phase reaction
system in the third step.

[0073]It suffices that the temperature condition ranges from -20 to
+150° C. The temperature condition is generally preferably in the
range of -10 to +125° C., more preferably 0 to +100° C.

[0074]The reaction time is generally 72 hours or less. As the reaction
time depends on the combination of the raw substrate material and the
acid catalyst and the adopted reaction conditions, it is preferable to
determine the time at which the raw substrate material has almost
disappeared as the end of the reaction while monitoring the progress of
the reaction by any analytical means such as gas chromatography,
thin-layer chromatography, liquid chromatography or nuclear magnetic
resonance.

[0075]The target optically active fluoroamine of the formula [6] can be
obtained by ordinary post treatment of the reaction-terminated liquid.
Further, the target compound can be purified to a high chemical purity,
as needed, by purification operation such as activated carbon treatment,
distillation, recrystallization or column chromatography.

[0076]In particular, the aldehyde of the formula [5] generated as a
by-product can be effectively removed by washing the acidic aqueous
solution of the target compound with an organic solvent such as toluene.
It is feasible to obtain the same effects as above by a simple operation
of performing the reaction in two-phase reaction system using an organic,
water-inmiscible solvent such as toluene. The target compound can be
obtained with high chemical purity in the form of a salt of the acid
catalyst by concentrating the recovered acidic aqueous solution of the
target compound, subjecting the concentrated residue to azeotropic
dehydration with an organic solvent such as ethyl acetate, and further
subjecting the dehydrated residue to hot washing with an organic solvent
such as ethyl acetate. In some cases, it may be efficient to recover the
target compound in the form of having its amino group protected with a
protecting group. As such an amino protecting group, there can be used
those described in the above-mentioned reference book.

[0077]The thus-obtained salt or protected form of the target compound can
be purified to a higher chemical purity by recrystallization etc.
Further, the salt or protected form of the target compound can be easily
converted to a free base or deprotected form by ordinary deionization
(neutralization) or deprotection.

[0078]As described above, there is provided according to the present
invention the production process of the optically active fluoroamine,
including the steps of forming the protected optically active
hydroxyamine (imine form, oxazolidine form or mixture thereof) by
dehydrative condensation of the optically active hydroxyamine and the
aldehyde, reacting the protected optically active hydroxyamine with
sulfuryl fluoride (SO2F2) in the presence of the tertiary amine
of carbon number 7 to 18 to thereby convert the protected optically
active hydroxyamine to the protected optically active fluoroamine, and
then, performing hydrolysis of the protected optically active fluoroamine
under the acidic conditions.

[0079]The present production process can be industrially easily carried
out by the use of the aromatic hydrocarbon group-containing aldehyde and
the tertiary amine having a carbon number of 8 to 12 and containing two
or more alkyl groups of 3 or more carbon atoms.

[0080]Further, there is provided the novel protected optically active
fluoroamine as a useful key intermediate for the present production
process.

[0082]The present invention will be described in more detail below by way
of the following examples. It should be noted that these examples are
illustrative and are not intended to limit the present invention thereto.

[0083]In the following examples, the abbreviations for chemical groups are
as follows: Me=methyl; Ph=phenyl; Boc=tert-butoxycarbonyl;
i-Pr=isopropyl; and Et=ethyl.

43.60 g (410.86 mmol, 1.03 eq) of an aldehyde of the following formula:

##STR00012##

and 0.76 g (4.00 mmol, 0.01 eq) of para-toluenesulfonic acid monohydrate
were added. The resulting liquid was stirred for 2 hours at room
temperature. The conversion rate of the reaction was determined to be
100% by gas chromatography of the reaction-terminated liquid. The
reaction-terminated liquid was vacuum concentrated and vacuum dried,
thereby yielding 66.77 g of a 83:17 mixture of an imine-protected
optically active hydroxyamine (imine form) of the following formula:

##STR00013##

and an oxazolidine-protected optically active hydroxyamine (oxazolidine
form, oxazolidine isomer ratio: about 3:2) of the following formula:

##STR00014##

The yield of the reaction product was quantitative (theoretical yield:
65.19 g). The gas chromatographic purity of the reaction product was
98.9%. The 1H-NMR measurement results of the reaction product (only
the 1H-NMR peaks specific to the imine form and to the oxazolidine
form) are indicated below.

[0086]A pressure-proof reaction vessel of stainless steel (SUS) was
charged with 30.00 g (assumed as 179.46 mmol, 1.00 eq) of the mixture of
the imine- and oxazolidine-protected optically active hydroxyamines of
the above formulas, 120 mL of acetonitrile and 28.51 g (220.60 mmol, 1.23
eq) of diisopropylethylamine, followed by immersing the reaction vessel
in a cooling bath of -78° C. and blowing 44.92 g (440.13 mmol,
2.45 eq) of sulfuryl fluoride (SO2F2) from a cylinder into the
reaction vessel. The resulting liquid was stirred for one night at room
temperature. The conversion rate of the reaction was determined to be
100% by gas chromatography of the reaction-terminated liquid. The
reaction-terminated liquid was vacuum concentrated. The concentration
residue was diluted with 100 mL of toluene, washed twice with 50 mL of a
saturated aqueous potassium carbonate solution and further washed twice
with 50 mL of water. The recovered organic phase was vacuum concentrated
and vacuum dried, thereby yielding 29.49 g of a protected optically
active fluoroamine of the following formula:

##STR00015##

The yield of the reaction product was 99%. The gas chromatographic purity
of the recovered organic phase was 92.1%. The 1H-NMR and
19F-NMR measurement results of the reaction product are indicated
below.

[0089]To 100 mL of methanol, 20.40 g (123.48 mmol, 1.00 eq) of the
protected optically active fluoroamine of the above formula and 61.18 g
(587.30 mmol, 4.76 eq) of 35% hydrochloric acid were added. The resulting
liquid was stirred for one night at room temperature. The conversion rate
of the reaction was determined to be 100% by 19F-NMR of the
reaction-terminated liquid. The reaction-terminated liquid was vacuum
concentrated. The concentration residue was diluted with 50 mL of water
and washed three times with 50 mL of toluene. With this, there was
obtained about 75 mL of an aqueous solution containing an optically
active fluoroamine hydrochloride salt of the following formula:

##STR00016##

[0090]To the whole (assumed as 123.48 mmol, 1.00 eq) of the aqueous
solution of the optically active fluoroamine hydrogen chloride salt of
the above formula, 100 mL of toluene, 73.44 g (725.76 mmol, 5.88 eq) of
triethylamine and 24.00 g (109.97 mmol, 0.89 eq) of Boc2O. The
resulting liquid was stirred for one night at room temperature. The
conversion rate of the reaction was determined to be 100% by 19F-NMR
of the reaction-terminated liquid. The reaction-terminated liquid was
separated into two phases. The recovered organic phase was washed twice
with 30 mL of water, vacuum concentrated and vacuum dried, thereby
yielding 19.71 g of a Boc-protected optically active fluoroamine (as a
crude product) of the following formula:

##STR00017##

The total yield of the crude product from the protected optically active
fluoroamine via the above two reaction steps was 90%. The gas
chromatographic purity of the crude product was 94.4%.

[0091]The crude product was subjected to solvent displacement treatment by
adding 30 mL of n-heptane to the whole (19.71 g) of the crude product and
vacuum concentrating the resulting liquid. Then, 12.44 g of a purified
product of the Boc-protected optically active fluoroamine was obtained by
recrystallization of the crude product from 40 mL of n-heptane. The
recovery of the purified product was 63%. The total yield of the purified
product from the optically active hydroxyamine via the above four
reactions steps (including the recrystallization) was 56%. The gas
chromatographic purity of the purified product was 99.4%. The optical
purity of the purified product was determined to be 98.6% ee by
19F-NMR of a Mosher's acid amide of the product (derived after the
Boc deprotection). The 1H-NMR and 19F-NMR measurement results
of the purified product are indicated below.

18.60 g (175.27 mmol, 1.03 eq) of an aldehyde of the following formula:

##STR00019##

and 0.32 g (1.68 mmol, 0.01 eq) of para-toluenesulfonic acid monohydrate
were added. The resulting liquid was stirred for one night at room
temperature. The conversion rate of the reaction was determined to be
100% by 1H-NMR of the reaction-terminated liquid. The
reaction-terminated liquid was vacuum concentrated and vacuum dried,
thereby yielding 36.14 g of a 57:43 mixture of an imine-protected
optically active hydroxyamine (imine form) of the following formula:

##STR00020##

and an oxazolidine-protected optically active hydroxyamine (oxazolidine
form, oxazolidine isomer ratio:about 2:1) of the following formula:

##STR00021##

The yield of the reaction product was quantitative (theoretical yield:
32.45 g). The gas chromatographic purity of the reaction product was
96.7%. The 1H-NMR measurement results of the reaction product (only
the 1H-NMR peaks specific to the imine form and the oxazolidine
form) are indicated below.

[0096]A pressure-proof reaction vessel of stainless steel (SUS) was
charged with the whole (assumed as 169.64 mmol, 1.00 eq) of the mixture
of the imine- and oxazolidine-protected optically active hydroxyamines of
the above formulas, 170 mL of acetonitrile and 87.00 g (673.17 mmol, 3.97
eq) of diisopropylethylamine, followed by immersing the reaction vessel
in a cooling bath of -78° C. and blowing 34.58 g (338.82 mmol,
2.00 eq) of sulfuryl fluoride (SO7F2) from a cylinder into the
reaction vessel. The resulting liquid was stirred for one night at room
temperature. The conversion rate of the reaction was determined to be 98%
by gas chromatography of the reaction-terminated liquid. The
reaction-terminated liquid was vacuum concentrated. The concentration
residue was diluted with 100 mL of toluene, washed twice with 50 mL of a
saturated aqueous potassium carbonate solution and further washed twice
with 50 mL of water. The recovered organic phase was vacuum concentrated
and vacuum dried, thereby yielding 35.00 g of a protected optically
active fluoroamine of the following formula:

##STR00022##

The yield of the reaction product was quantitative (theoretical yield:
32.78 g). The gas chromatographic purity of the reaction product was
93.8%. The 1H-NMR and 19F-NMR measurement results of the
reaction product are indicated below.

[0099]The whole (assumed as 169.64 mmol, 1.00 eq) of the protected
optically active fluoroamine of the above formula and 175.82 g (1687.79
mmol, 9.95 eq) of 35% hydrochloric acid were added to 70 mL of toluene.
The resulting liquid was stirred for one night at 50° C. The
conversion rate of the reaction was determined to be 100% by 19F-NMR
of the reaction-terminated liquid. The reaction-terminated liquid was
separated into two phases. The recovered aqueous phase was vacuum
concentrated and subjected three times to azeotropic dehydration (vacuum
concentration) with 50 mL of ethyl acetate. The thus-obtained residue was
washed by stirring with 75 mL of ethyl acetate for 1 hour under reflux,
and then, subjected to hot filtration and vacuum drying, thereby yielding
17.99 g of an optically active fluoroamine hydrogen chloride salt of the
following formula:

##STR00023##

The total yield of the product from the optically active hydroxyamine via
the above three reaction steps was 75%. The gas chromatographic purity of
a free base of the product was 97.3%. The optical purity of the product
was determined to be 99.9% ee by gas chromatography of a Mosher's acid
amide of the product (derived after the deionization). The mass spectrum
of the free base (by CI method) was 106 (M+1). The 1H-NMR and
19F-NMR measurement results of the product are indicated below.

[0103]A pressure-proof reaction vessel of stainless steel (SUS) was
charged with 1.000 g (6.127 mmol, 1.00 eq) of the mixture of the imine-
and oxazolidine-protected optically active hydroxyamines of the above
formulas, 6 mL of acetonitrile and 2.468 g (24.390 mmol, 3.98 eq) of
triethylamine, followed by immersing the reaction vessel in a cooling
bath of -78° C. and blowing 1.807 g (17.705 mmol, 2.89 eq) of
sulfuryl fluoride (SO2F2) from a cylinder into the reaction
vessel. The resulting liquid was stirred for one night at room
temperature. The conversion rate of the reaction was determined to be 96%
by gas chromatography of the reaction-terminated liquid. The
reaction-terminated liquid was diluted with 20 mL of ethyl acetate,
washed with 10 mL of a saturated aqueous potassium carbonate solution and
further washed three times with 10 mL of water. The recovered organic
phase was vacuum concentrated and vacuum dried, thereby yielding 0.813 g
of a 24:76 mixture of a protected optically active fluoroamine of the
following formula:

##STR00026##

and a quaternary ammonium salt of the following formula:

##STR00027##

The yield of the product was 44% (protected optically active fluoroamine:
11%, quaternary ammonium salt: 33%). The 1H-NMR measurement results
of the product (only the 1H-NMR peaks specific to the protected
optically active fluoroamine and to the quaternary ammonium salt) are
indicated below.

[0105]It is seen from the above results that: the target compound was
produced, but the product yield remained low, in Comparative Example 1
using triethylamine i.e. tertiary amine of carbon number less than 7;
whereas the target protected optically active fluoroamine was produced
with much higher yield in the production process of the present invention
(Examples).